title: Progesterone inhibition of voltage-gated calcium channels is a potential neuroprotective mechanism against excitotoxicity.
abstract: The therapeutic use of progesterone following traumatic brain injury has recently entered phase III clinical trials as a means of neuroprotection. Although it has been hypothesized that progesterone protects against calcium overload following excitotoxic shock, the exact mechanisms underlying the beneficial effects of progesterone have yet to be determined. We found that therapeutic concentrations of progesterone to be neuroprotective against depolarization-induced excitotoxicity in cultured striatal neurons. Through use of calcium imaging, electrophysiology and the measurement of changes in activity-dependent gene expression, progesterone was found to block calcium entry through voltage-gated calcium channels, leading to alterations in the signaling of the activity-dependent transcription factors NFAT and CREB. The effects of progesterone were highly specific to this steroid hormone, although they did not appear to be receptor mediated. In addition, progesterone did not inhibit AMPA or NMDA receptor signaling. This analysis regarding the effect of progesterone on calcium signaling provides both a putative mechanism by which progesterone acts as a neuroprotectant, as well as affords a greater appreciation for its potential far-reaching effects on cellular function.
authors.affiliation: Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA. luom0025@umn.edu
authors.forename: Jessie I
authors.initials: JI
authors.lastname: Luoma
authors.forename: Brooke G
authors.initials: BG
authors.lastname: Kelley
authors.forename: Paul G
authors.initials: PG
authors.lastname: Mermelstein
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000503:physiopathology*; D001930:Brain Injuries / Q000188:drug therapy; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects*; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D017930:Genes, Reporter; D018698:Glutamic Acid / Q000494:pharmacology; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D016202:N-Methylaspartate / Q000494:pharmacology; D050778:NFATC Transcription Factors / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D009543:Nifedipine / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D011374:Progesterone / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D017362:Cyclic AMP Response Element-Binding Protein; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D050778:NFATC Transcription Factors; D018696:Neuroprotective Agents; D018698:Glutamic Acid; D011374:Progesterone; D016202:N-Methylaspartate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D008156:Luciferases; D009543:Nifedipine; D011188:Potassium